Process for the preparation of optically pure or optically enriched enantiomers of sulphoxide compounds

ABSTRACT

A process for preparation of optically pure or optically enriched enantiomers of sulphoxide compounds of formula (I), such as omeprazole and structurally related compounds, as well as their salts and hydrates. The said process comprises
         a) providing, a mixture of enantiomers of the sulphoxide compound of formula (I) as starting material, in an organic solvent; said enantiomers having R and S configurations at the sulfur atom of the sulphoxide group;   b) treating the mixture of enantiomers, in the organic solvent, with a chiral host;   c) separating the adduct formed by the enantiomer and the chiral host;   d) if desired, repeating the operation of step (b);   e) treating the adduct obtained in step (c) or (d) with metal base selected from Group I and Group II metal, thereby obtaining metal salt of one of the optical isomers of the sulphoxide compound in optically pure or optically enriched form;   f) optionally, converting the Group I metal salt of optically pure or optically enriched form the optical isomers of the sulphoxide compound obtained in step (e) to magnesium salt.

This application is a National Stage Application of PCT/1N20078/004245,filed Oct. 5, 2006, which claims benefit of Serial No. 676/KOL/2006,filed Jul. 5, 2006 in India and which application(s) are incorporatedherein by reference. To the extent appropriate, a claim of priority ismade to each of the above disclosed applications.

FIELD OF THE INVENTION

The present invention relates to a process for preparation of opticallypure or optically enriched enantiomers of sulphoxide compounds, such asomeprazole and structurally related compounds, as well as their saltsand hydrates.

BACKGROUND OF THE INVENTION

Substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles of formula(I) are useful

as inhibitors of gastric acid secretion.wherein R₁, R₂ and R₃ are the same or different and selected fromhydrogen, alkyl, alkylthio, alkoxy optionally substituted by fluorine,alkoxyalkoxy, dialkylamino, and halogen; R₄-R₇ are the same or differentand selected from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy,alkylcarbonyl, alkoxycarbonyl, and trifluoroalkyl.

For example, the compounds with generic names omeprazole, lansoprazole,rabeprazole, pantoprazole are used in the treatment of peptic ulcer.These compounds have a chiral center at the sulphur atom and thus existas two optical isomers, i.e. enantiomers.

It has been well recognized in several pharmacologically activecompounds that one of the enantiomer has superior biological propertycompared to the racemate and the other isomer.

For example, omeprazole (CAS Registry No. 73590-58-6), chemically knownas5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl}-1H-benzimidazole,is a highly potent inhibitor of gastric acid secretion. It has a chiralcenter at the sulphur atom and exists as two enantiomers(S)-(−)-omeprazole and (R)-(+)-omeprazole. It has been shown that the(S)-enantiomer of omeprazole has better pharmacokinetic and metabolicproperties compared to omeprazole. The (S)-enantiomer of omeprazolehaving generic name esomeprazole is marketed by Astra Zeneca in the formof magnesium salt under the brand name NEXIUM®. Therefore, there is ademand and need for an industrial scale process for manufacturingesomeprazole.

The methods of synthesis of racemic sulphoxide compounds of formula (I)are very successful for a large-scale industrial manufacture. However,the production of optically pure sulphoxide compounds of formula (I) isnot easy.

The prior art methodologies for the preparation of single enantiomers ofsulphoxides of formula (I) are based on enantioselective or chiralsynthesis, optical resolution of the racemate, separation by convertingthe racemate to diastereomers, or by chromatography.

For example, some of the earliest prior art on enantioselectivesynthesis of the single enantiomers of sulphoxides of formula (I)described in Euro. J. Biochem. 166, (1987), 453, employed asymmetricsulphide oxidation process developed and reported by Kagan andco-workers in J. Am. Chem. Soc. 106 (1984), 8188. The process disclosedtherein provides sulphoxide products in an enantiomeric excess of onlyabout 30%, which upon several recrystallization steps yielded opticallypure sulphoxide up to an e.e. of 95%. The oxidation was performed byusing tert-butyl hydroperoxide as oxidizing agent in the presence of oneequivalent of a chiral complex obtained from Ti(OiPr)₄/(+) or(−)-diethyl tartrate/water in the molar ratio of 1:2:1. A minimum of 0.5equivalent of titanium reagent was found to be a must for obtaining veryhigh enantioselectivity.

An improvement in the above oxidation process to obtain higherenantioselectivity was reported by Kagan and co-workers in Tetrahedron(1987), 43, 5135; wherein tert-butyl hydroperoxide was replaced bycumene hydroperoxide. In their further study reported in Synlett (1990),643; Kagan and co-workers found that high enantioselectivity can beobtained if the temperature is maintained between −20° C. to −40° C.,and methylene chloride is used as a solvent.

In contrary to Kagan's observation of requirement of low temperature andchlorinated solvent like methylene chloride for high enantioselectivityof the chiral oxidation, Larsson et al in U.S. Pat. No. 5,948,789(equivalent to PCT publication WO 96/02535) have described anenantioselective process for the synthesis of the single enantiomers ofcompound of formula (I) by the chiral oxidation of the pro-chiralsulphide of formula (Ia) utilizing a chiral titanium (IV) isopropoxidecomplex in solvent systems such as toluene, ethyl acetate at 20-40° C.,and most importantly a base like amine such as triethyl amine ordiisopropyl amine.

Although the formation of % e.e. of the desired isomer is satisfactory,the method suffers from the disadvantage (a) of low chemical conversion;(b) formation of undesired sulphide and sulfone impurities insubstantial amounts, necessitating further purification by one or moretedious crystallization.

It is obvious from the above that such conversions which result in lowchemical conversion and require costly metal complex and protractedpurification, surely, is not desirable process for making a product suchas optically active prazole in an industrial scale.

WO 96/17076 teaches a method of enantioselective biooxidation of thesulphide compound (Ia), which is effected by the action of Penicilliumfrequentans, Brevibacterium paraffinolyticum or Mycobacterium sp.

WO 96/1707 teaches the bioreduction of the racemic omeprazole to anenantiomer or enantiomerically enriched sulphide of formula (Ia), whichis effected by the action of Proteus vulgaris, Proteus mirabilis,Escherichia coli, Rhodobacter capsulatus or a DMSO reductase isolatedfrom R. capsulatus.

The separation of enantiomers of omeprazole in analytical scale isdescribed in Marie et al.; J. Chromatography, 532, (1990), 305-19. WO03/051867 describes a method for preparation of an enantiomerically pureor optically enriched enantiomer of either omeprazole, pantoprazole,lansoprazole, or raberpazole from a mixture containing the same usingmeans for simulated moving bed chromatography with a chiral stationaryphase such as amylose tris(S)-methylbenzycarbanmate. However,chromatographic methods are not suitable for large-scale manufacture ofthese prazoles.

The optical resolution methods taught in the art for separating theenantiomers of certain 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazolesof formula (I) utilizes the diastereomer method, the crystallizationmethod or the enzyme method.

The resolution process disclosed in DE 4035455 and WO 94/27988 involveconverting the racemate 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazolesto a diastereomeric mixture using a chiral acyl group, such asmandeloyl, and the diastereomers are separated and the separateddiastereomer is converted to the optically pure sulphoxide byhydrolysis.

The method suffers from the following disadvantages,

-   -   (i) the resolution process involves additional steps of        separation of diastereomeric mixture, and hydrolysis of the        N-substituent in separated diastereomer,    -   (ii) the conversion of the racemate to diastereomeric acyl        derivative is low yielding (˜40%),    -   (iii) the diastereomer from the unwanted (R)-enantiomer is        separated and discarded,        WO 2004/002982 teaches a method for preparation of optically        pure or optically enriched isomers of omeprazole by reacting the        mixture of optical isomers with a chelating agent (D)-diethyl        tartrate and transition metal complex titanium (IV) isopropoxide        to form a titanium metal complex in an organic solvent such as        acetone in presence of a base such as triethyl amine, which is        then converted to salt of L-mandelic acid. The mandelic acid        salt of the titanium complex of optical isomer derived from        (S)-enantiomer of omeprazole gets precipitated, which is        separated and purified to obtain chiral purity of about 99.8%.

Optically active 1,1′-bi-2-naphthol (BINOL) and its derivatives areuseful as chiral ligands in catalysts for asymmetric reactions to hostsfor molecular recognition and enantiomer separation, and oftenintermediates for the synthesis of chiral molecules.

BINOL is known to form crystalline complexes with a variety of organicmolecules through hydrogen bonding. The (S) and/or (R) BINOL was foundto be useful as a chiral host for enantioselective complexation. Theapplication of BINOL in resolution of omeprazole is disclosed Deng et alin CN 1223262.

The Chinese patent application CN 1223262 (Deng et al) teaches theutility of chiral host compounds such as dinaphthalenephenols (BINOL),diphenanthrenols or tartaric acid derivatives in the resolution ofprazoles. The method consists of formation of 1:1 solid complex betweenthe chiral host and one of the enantiomer of the prazole, the guestmolecule. The other enantiomer remains in the solution. The racemicprazole is treated with the chiral host in a mixture of solventcomprising of aromatic hydrocarbon solvents such as benzene, alkylsubstituted benzene or acetonitrile and, hexane. The solid complex isseparated from the solution, and dissolved again in afresh solventsystem by heating to 60-130° C. and then keeping at −20-10° C. for 6-36hrs to obtain higher e.e. value for the solid complex. The process isrepeated many times to obtain high e.e. values for the solid complex.The host and the guest in the solid complex are separated by columnchromatography. The final separated single enantiomer of the prazole isthen recrystallized from a mixture of methylene chloride or chloroformand, ether.

In a later publication in Tetrahedron Asymmetry 11 (2000), 1729-1732 theinventors of the above mentioned Chinese patent application reported theresolution of omeprazole using (S)-BINOL. An inclusion complex of(S)-BINOL and (S)-omeprazole was obtained as a grey-blue complex with90.3% e.e. by mixing racemate omeprazole and (S)-(−)-BINOL in the moleratio 1:1.5, in a solvent mixture of benzene:hexane (v/v=4:1) at 110° C.The inclusion complex obtained was further purified by recrystallizationin benzene:hexane (v/v, 1:1) and separated on a silica gel column toyield (S)-(−)-omeprazole with 98.9% e.e. and 84.1% overall yield. The(S)-(−)-omeprazole so obtained was recrystallized in water to obtain asa white powder with 99.2% e.e.

In this publication, the authors have reported their observation ofcriticality of the benzene:hexane solvent ratio in obtaining theinclusion complex and the enantioselectivity. The authors reportedlyhave obtained the best enantioselectivity of 90.3% e.e. when the solventratio of benzene:hexane is 4:1 and the mole ratio of racemate omeprazoleand (S)-(−)-BINOL is 1:1.5.

Further, by comparing the IR stretching frequencies observed for S═Obond in racemate omeprazole (1018 cm⁻¹) and its inclusion complex with(S)-(−)-BINOL (1028 cm⁻¹), the authors have concluded that the S═O bondwhich involved in a N—H . . . O═S hydrogen bond does not attribute theformation of hydrogen bonding in the inclusion complex, and the chiralrecognition in the inclusion complex may occur via formation ofhydrogen-bonded supramolecular chiron.

The method described in the above-mentioned Chinese patent applicationsuffers in that,

-   -   (i) due to very low e.e. value for the solid complex obtained        for the first time, the complexation process has to be repeated        till the desired e.e. value is obtained,    -   (ii) to separate the host and the guest, one has to take        recourse to tedious chromatographic methods,    -   (iii) overall the resolution involves several operations of        complex formation, separation, purification by chromatography        and recrystallization,    -   (iv) For the purpose of chromatography the amount silica and the        solvent required is exorbitant    -   (v) with more operation steps, there is considerable material        loss leading to lowering of the overall yield, which is not        satisfactory for a commercial scale production,    -   (vi) the use of hexane with low flash point is not recommended        for industrial processes,    -   (vii) volumes of the solvents to be handled having low flash        point are quite large, necessitating special design of plant and        machinery for safety,    -   (viii) benzene is carcinogenic and is listed as a class 1        solvent in ICH guideline.

Taking these considerations, the process disclosed in the CN 1223262(Deng et al) does not give cost effective and eco-friendly method ofmanufacture.

It is evident from the above that there is a need for synthesizingoptically pure sulphoxide compounds of formula (I), their salts, andtheir hydrates by a process that is (a) cost effective (b) simple (c)easy to operate (d) eco-friendly, (e) consistently give good yields andpurity with minimum variables (e) highly reproducible.

The present invention provides such a solution.

OBJECT OF THE INVENTION

The object of the invention is to provide an improved method for themanufacture of single enantiomers of the sulphoxide compounds of theformula (I) and their pharmaceutically acceptable salts and hydrates,thereby resulting in significant economic and technological improvementover the prior art methods.

More specifically, the object of the invention is to manufacture singleenantiomers of Omeprazole, Rabeprazole, Lansoprazole or Pantoprazolecovered by the formula (I), and pharmaceutically acceptable salts andhydrates.

SUMMARY OF THE INVENTION

Thus, according to one aspect of present invention there is provided aprocess for preparation of an optically pure or optically enrichedenantiomer of a sulphoxide compound of formula (I), said processcomprises:

-   -   a) providing, a mixture of optical isomers of the sulphoxide        compound of formula (I) as starting material, in an organic        solvent; the different optical isomers having R and S        configurations at the sulfur atom of the sulphoxide group;    -   b) reacting the mixture of optical isomers, in the organic        solvent, with a chiral host;    -   c) separating the adduct formed by the enantiomer and the chiral        host;    -   d) if desired, repeating the operation of step (b);    -   e) treating the adduct obtained in step (c) or (d) with a metal        base selected from Group I or Group II metal, thereby obtaining        the metal salt of the enantiomer of the sulphoxide compound in a        substantially optically pure or optically enriched form;    -   f) optionally, converting the Group I metal salt of        substantially optically pure or optically enriched enantiomer of        the sulphoxide compound obtained in step (e) to magnesium salt.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 illustrates an infrared (IR) spectrum of racemic omeprazole.

FIG. 2 illustrates an IR spectrum of S-BINOL.

FIG. 3 illustrates an IR spectrum of the host-guest inclusion complexincluding S-BINOL and esomeprazole.

FIG. 4 illustrates an X-ray powder diffraction pattern of the host-guestinclusion complex including S-BINOL and esomeprazole.

FIG. 5 illustrates an X-ray powder diffraction pattern of an amorphousform of esomeprazole magnesium salt.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a process for preparation of an opticallypure or optically enriched enantiomer of a sulphoxide compound offormula (I). Intermediates in the processes of this invention are alsopart of this invention, as are their salts and hydrates. The sulphoxidecompounds suitable as substrates for the process of this aspect of theinvention include, for example, omeprazole, lansoprazole, pantoprazole,rabeprazole In a preferred embodiment in step (b), the chiral host isoptically pure or optically enriched (S)-(−)-BINOL or (R)-(+)-BINOL.

In a more preferred embodiment, the invention provides a specificprocess for preparing a substantially optically pure or opticallyenriched form of omeprazole and its pharmaceutically acceptable salts.In other preferred aspect, the invention also provides an amorphous formof magnesium salt of esomeprazole trihydrate.

The process is depicted in the following Scheme 1

In their endeavor to obtain optically pure enantiomer of the sulphoxidecompounds of the formula (I), for example the (S)-omeprazole fromracemate omeprazole or optically enriched omeprazole by resolutionmethod using BINOL, the present inventors surprisingly found that,

-   -   (i) use of mixture of toluene and cyclohexane significantly        improved the e.e. value of the inclusion complex of (S)-BINOL        and (S)-omeprazole,    -   (ii) the inclusion complex of (S)-BINOL and (S)-omeprazole can        be directly converted to Group I or Group II metal salt of        (S)-omeprazole without any further purification of the complex        by recrystallization and separation of the host and the guest by        chromatography,    -   (iii) the (S)-BINOL and the other isomer (R)-omeprazole could be        recovered and recycled,    -   (iv) the methodology could be conveniently adopted for other        sulphoxide compounds such as Rabeprazole, Lansoprazole, or        Pantoprazole,

The present method addresses the drawbacks of the resolution usingchiral host disclosed in the CN 1223262 by,

-   -   (i) providing the chiral complex in very high e.e. in minimum        number of operational steps,    -   (ii) obviates the usage of hexane which is having low flash        point,    -   (iii) utilizes cyclohexane which is a preferred solvent over        hexane as the allowed limit of residual solvent for cyclohexane        is 3880 ppm, while it is 290 ppm for hexane, in the ICH        guideline,    -   (iv) significantly increases the overall yield through        recovering of the chiral material and racemization of the        undesired isomer,

In one embodiment of the process aspect of the invention, the startingmaterial is a compound of the formula (I). In one variant, R₁, R₂ aremethyl; R₂ and R₅ are methoxy; and R₄, R₆, and R₇ are hydrogen. Inanother variant R₄, R₅, R₆, and R₇ are hydrogen; R₁ is hydrogen; R₃ ismethyl, and R₂ may be —O(CH₂)₃OCH₃ or —OCH₂CF₃. In a further variant,R₁, R₄, R₆ and R₇ are hydrogen; R₅ is difluoromethoxy; and R₂ and R₃ aremethoxy. Specific starting materials that are suitable includeomeprazole, lansoprazole, rabeprazole, and pantoprazole.

Initially, a solution of the racemic mixture of the sulphoxide compoundof formula (I) is provided in an organic solvent, by suspending ordissolving the compound of formula (I). As used herein, the term“solvent” may be used to refer to a single compound or a mixture ofcompounds. Suitable organic solvents are preferably alkyl benzenes andcyclohexane. Among the alkyl benzenes, toluene and xylene are preferred.Preferably, the organic solvent is at least a mixture of alkyl benzenesuch as toluene or xylene and cyclohexane. More preferably, the organicsolvent is a mixture of toluene and

cyclohexane.

Suitable chiral host include 1,1′-bi-2-naphthol (BINOL),diphenanthrenols or tartaric acid derivatives. Preferably, the(S)-(−)-BINOL or (R)-(+)-BINOL are used. The (S)-(−)-BINOL or(R)-(+)-BINOL may be used in optically pure or optically enriched form.

By mixing the chiral host with the racemate sulphoxide of formula (I)(guest molecules) in the solvent and gently warming to about 50-55° C.,the chiral host forms an adduct with one of the enantiomer by a chiralrecognition or molecular recognition process. The adduct known as ahost-guest inclusion complex is formed via selectively and reversiblyincluding the chiral guest molecules in host lattice throughnon-covalent interactions such as hydrogen bonding.

The host-guest inclusion complex crystallizes out as solid compound uponlowering the temperature, from ambient to about 0-10° C. The complex wasseparated out, washed with the solvent. If desired, the separatedhost-guest inclusion complex may be re-dissolved in the solvent andcrystallized out.

By these operations, the process achieves the physical separation of thetwo enantiomers of the sulphoxide compound of formula (I), oneenantiomer in the form of a host-guest inclusion complex and the otherenantiomer remains in the solution.

If only one enantiomer is desired, the other may be racemized, in anyway known to those skilled in the art, to obtain the starting materialsulphoxide of formula (I). The racemization permits increasedutilization of the material since the racemized product may be re-usedin the process as described.

The adduct is treated with a metal base (MB) where M is the metal ofGroup I or Group II in an alcoholic solvent selected from methanol,ethanol, isopropanol, and tent-butyl alcohol or mixtures thereof toobtain the corresponding metal salt of optically pure optically enrichedenantiomer of the sulphoxide compound of formula (I).

In one embodiment, the adduct is treated with a metal base of Group Imetal to obtain an alkali metal salt of optically pure opticallyenriched enantiomer of the sulphoxide compound of formula (I). Thealkali metal salt is then converted to the magnesium salt.

The preferred metal base of Group I metal are potassium hydroxide orsodium hydroxide.

In another embodiment, the adduct is directly converted to the magnesiumsalt of optically pure optically enriched enantiomer of the sulphoxidecompound of formula (I), for instance, by treating with magnesium inmethanol.

In a further embodiment, the adduct is first converted to an alkalineearth metal salt such as barium or calcium by treating with their oxideor hydroxide in an alcoholic solvent, and subsequently converted to themagnesium salt.

The preferred embodiment of the process aspect of the invention involvespreparation of the (S) enantiomer of omeprazole, known as esomeprazole,and its salts. The scheme 2 illustrates the preferred processcontemplated by the inventors.

Racemic omeprazole, was treated with the chiral host (S)-(−)-BINOL, intoluene-cyclohexane (4:1 v/v). A bluish gray adduct, the inclusioncomplex was formed between the (S)-BINOL and (S)-isomer of omeprazole,which was separated by filtration and washed with a mixture ofcyclohexane and toluene. The optical purity of esomeprazole in thecomplex as measured by HPLC was not less than 99.5% e.e.

The IR-spectra of racemic omeprazole, (S)-BINOL and the host-guestinclusion complex is provided in FIGS. 1, 2, and 3 respectively. Thereis no significant difference in the stretching frequency of S═O bond inracemate omeprazole (1017 cm⁻¹) as compared to the stretching frequencyof 1028 cm⁻¹ in the inclusion complex.

The adduct isolated is treated with potassium hydroxide or sodiumhydroxide in an alcoholic solvent selected from methanol, ethanol,isopropanol, and tent-butyl alcohol or mixtures thereof to obtain thepotassium or sodium metal salt of optically pure optically enrichedenantiomer of the sulphoxide compound of formula (I).

The sodium or potassium salt of optically pure optically enrichedenantiomer of the sulphoxide compound of formula (I) is converted tomagnesium salt by treating with MgSO₄.

In another embodiment the (S)-omeprazole-(S)-(−)-BINOL adduct isconverted directly to its magnesium salt by treating with magnesium inmethanol as depicted in Scheme 2.

The esomeprazole magnesium obtained by the process is in an amorphousform characterized by powder X-ray diffraction pattern given in FIG. 5.

Alternatively, if (R)-enantiomer of omeprazoele is desired,(R)-(+)-BINOL may be used in the process described above.

The following examples illustrate the practice of the invention withoutbeing limiting any way.

EXAMPLE 1 Preparation of (S)-omeprazole-(S)-(−)-BINOL complex

Omeprazole (100 g, 0.2898 mole) was added to a mixture of toluene (1600ml) and cyclohexane (400 ml) in a round bottom flask kept at 25-30° C.(S)-(−)-BINOL (124.3 g, 0.4346 mole) was added and the content warmed toabout 50-55° C. with stirring for 30-45 minutes. The content of theflask was allowed to attain the ambient temperature and then cooled to0-5° C. with stirring for about an hour. The(S)-omeprazole-(S)-(−)-BINOL complex crystallizes out, filtered andwashed with a mixture of cyclohexane/toluene (1:4, v/v) pre-cooled to0-5° C. The (S)-omeprazole-(S)-(−)-BINOL complex was dried at 35-40° C.under reduced pressure. The e.e. of (S)-omeprazole in the complex wasfound to be 99.5%. Yield: 85%.

The IR spectrum of the complex is given in FIG. 3. The powder X-raydiffraction pattern is given in FIG. 4

EXAMPLE 2 Preparation of Esompeprazole Potassium Salt

To a solution of potassium hydroxide (31 g, 0.5535 mole) in methanol(500 ml) kept in a round bottom flask was added(S)-omeprazole-(S)-(−)-BINOL complex (100 g, 0.1584 mole) with stirringat 25-30° C. The content of the flask were stirred for about 2-2.5 hrsat 25-30° C. and then cooled to 0-5° C. and stirred for a further periodof about 1-1.5 hrs. The potassium salt of esomeprazole was filtered,washed with cold methanol (50 ml), followed by washing with cold acetone(100 ml) and dried under suction. The optical purity of esompeprazolepotassium as tested by HPLC was not less than 99.5%. Yield: 80%.

EXAMPLE 3 Preparation of Esomeprazole Magnesium Salt

To a solution of esomeprazole potassium salt (100 g, 0.261 mole) inmethanol (500 ml) kept in a round bottom flask, was added magnesiumsulphate heptahydrate (64.1 g, 0.26 mole) at 25-30° C. and stirred for1.5-2 hrs. The insoluble material formed was filtered off and thefiltrate was passed through a 0.45 micron membrane filter. To thefiltrate, water (1300 ml) was added and stirred at 25-30° C. for 1-1.5hrs, cooled to 0-5° C., and stirred for a further period of 1-1.5 hrs.The solid formed was collected by filtration and washed with water anddried under reduced pressure at 40-45° C. to obtain the esomeprazolemagnesium salt.

Yield: 45%.

Optical purity: 100%

Optical rotation: [α]_(D)=−142.04° at 25° C. and c=0.5% in methanol

e.e.: 100%

The esomeprazole magnesium salt obtained is in an amorphous form ascharacterized by its powder X-ray diffraction pattern given in FIG. 5.

The moisture content of the product is 7.5% by TGA, indicating that theproduct is a trihydrate.

EXAMPLE 4 Preparation of Esomeprazole Magnesium Salt

To a suspension of Magnesium turnings (0.5 g, 0.0208 mole) in methanol(15 ml) was added methylene chloride (0.5 ml), stirred for about 1.5-2hrs at 55-60° C. (S)-omeprazole-(S)-(−)-BINOL complex (2 g, 0.0030moles) was added and stirred for 45-60 minutes. The insoluble salts werefiltered off. To the combined filtrate was added water (30 ml), stirredfor about 45-60 minutes and cooled to 0-5° C. to obtain a solid, whichwas collected by filtration and dried.

Yield: 35.4%

e.e.: 99.6%

optical purity: 99.8%

EXAMPLE 5 Preparation of (S)-rabeprazole-(S)-(−)-BINOL complex

To a mixture of toluene (100 ml) and cyclohexane (150 ml) in a roundbottom flask was added rabeprazole (10 g, 0.0278 mole), and gentlywarmed to 48-52° C. for 30-45 minutes. The reaction mass was cooled to25-30° C. and further cooled to 3-8° C., stirred for 45-60 minutes toisolate a solid product, which was washed with cold cyclohexane-toluene(1:1 v/v). The product was dried at 35-40° C. under reduced pressure.

Yield: 55.6%

e.e.: 99.8%

optical purity: 99.9%

The invention claimed is:
 1. A process for preparation of an optically pure or optically enriched enantiomer of a sulphoxide compound of formula (I), said process consisting essentially of: a) providing a mixture of enantiomers of the sulphoxide compound of formula (I) as starting material, in an organic solvent; said enantiomers having R and S configurations at the sulfur atom of the sulphoxide group; b) treating the mixture of enantiomers, in the organic solvent, with (S)-(−)-BINOL; c) separating the adduct formed by the enantiomer and (S)-(−)-BINOL; d) if desired, repeating the operation of step (b); e) treating the adduct obtained in step (c) or (d) with metal base selected from Group I and Group II metal, thereby obtaining metal salt of one of the optical isomers of the sulphoxide compound in optically pure or optically enriched form; f) optionally, reacting the Group I metal salt of optically pure or optically enriched form the optical isomers of the sulphoxide compound obtained in step (e) to magnesium salt

wherein the substituents in Formula (I) can be same or different selected from the following where R₁ is H or -Me; R₂ is H or —OMe; R₃ is H, -Me, or —OMe; R₄ is H or —OMe; R₅ is H, —OMe, or difluoromethoxy; R₆ is H, —O(CH₂)₃OCH₃, or —OCH2CF₃; and R₇ is H or CH₃.
 2. A process according to claim 1, wherein the optical purity of the enantiomer of the sulphoxide compound of formula (I) is at least 99.5%.
 3. The process according to claim 1, wherein R₁ and R₃ are methyl; R₂ and R₅ are methoxy; and R₄, R₆, and R₇ are hydrogen.
 4. The process according to claim 1, wherein R₁, R₄, R₆, and R₇ are hydrogen; R₅ is difluoromethoxy; and R₃ and R₄ are methoxy.
 5. The process according to claim 1, wherein R₁, R₂, R₃, and R₄ are hydrogen.
 6. The process according to claim 5, wherein R₅ is hydrogen and R₇ is methyl.
 7. The process according to claim 6, wherein R₆ is —O(CH₂)₃OCH₃.
 8. The process according to claim 6, wherein R₆ is —OCH₂CF₃.
 9. The process according to claim 1, wherein the organic solvent is a mixture of alkyl benzene and cyclohexane.
 10. The process according to claim 9, wherein the organic solvent is a mixture of toluene and cyclohexane.
 11. The process according to claim 1, wherein the reaction of the adduct to the Group I or Group II metal salt of the enantiomer by treating with a oxide or hydroxide of Group I or Group II metal is carried out in an alcoholic solvent selected from methanol, ethanol, isopropanol, and isobutyl alcohol.
 12. The process according to claim 11 wherein the Group I metal is selected from lithium, sodium, and potassium.
 13. The process according to claim 11, wherein the Group II metal is selected from magnesium, calcium and barium.
 14. The process according to claim 1, wherein said starting material is omeprazole.
 15. The process according to claim 14, wherein the said adduct is a host-guest complex of (S) enantiomer of omeprazole with (S)-(−)-BINOL.
 16. The process according to claim 14, wherein the host-guest complex of (S) enantiomer of omeprazole with (S)-(−)-BINOL is treated with potassium hydroxide in methanol.
 17. The process according to claim 15, wherein the host-guest complex of (S) enantiomer of omeprazole with (S)-(−)-BINOL is treated with magnesium in methanol.
 18. The process according to claim 14, wherein the said product is potassium salt of (S) enantiomer of omeprazole.
 19. The process according to claim 14, wherein the product is magnesium salt of esomeprazole.
 20. The process according to claim 11, wherein said solvent is methanol.
 21. The process of claim 1, wherein the mixture in b) consists of the mixture of enantiomers, the organic solvent, and the (S)-(−)-BINOL.
 22. The process of claim 21, wherein the mixture in a) consists of the mixture of enantiomers and the organic solvent.
 23. The process of claim 20, wherein the solvent consists of alkyl benzene and cyclohexane.
 24. A process for preparing an optically pure or optically enriched enantiomer of a sulphoxide compound of formula (I)

where R₁ is H or -Me; R₂ is H or —OMe; R₃ is H, -Me, or —OMe; R₄ is H or —OMe; R₅ is H, —OMe, or difluoromethoxy; R₆ is H, —O(CH₂)₃OCH₃, or —OCH2CF₃; R₇ is H or CH₃; and the substituents can be the same or different; the process comprising: providing a mixture consisting of enantiomers of the sulphoxide compound of formula (I) and an organic solvent, the enantiomers having R and S configurations at the sulfur atom of the sulphoxide group; adding (S)-(−)-BINOL to the mixture consisting of enantiomers of the sulphoxide compound of formula (I) and an organic solvent to form a mixture consisting of mixture consisting of enantiomers of the sulphoxide compound of formula (I), the organic solvent, the (S)-(−)-BINOL, and an adduct of the enantiomer and (S)-(−)-BINOL; separating the adduct formed by the enantiomer and (S)-(−)-BINOL; optionally, repeating the adding of (S)-(−)-BINOL and obtaining the adduct; treating the adduct obtained with metal base selected from Group I and Group II metal and obtaining a metal salt of one of the optical isomers of the sulphoxide compound in optically pure or optically enriched form; optionally, reacting the Group I metal salt of optically pure or optically enriched form the optical isomers of the sulphoxide compound obtained in step (e) to magnesium salt. 